Pleural mesothelioma (PM) is a highly aggressive asbestos-related malignancy with poor prognosis and limited early diagnostic options. In this study, network toxicology and integrated multi-omics analyses were used to investigate the molecular mechanisms by which chrysotile, crocidolite, and amosite may induce PM, and to identify diagnostic core genes. Asbestos-related targets from the Comparative Toxicogenomics Database (CTD) database were integrated with Gene Expression Omnibus (GEO) transcriptomic datasets, followed by differential expression analysis, weighted gene co-expression network analysis, protein-protein interaction analysis, functional enrichment, machine-learning screening, and SHAP interpretation. Candidate targets were mainly enriched in inflammation-related pathways, including cytokine regulation, complement and coagulation cascades, NF-κB, TNF, and IL-17 signalling. Adrenergic receptor beta 2 (ADRB2), LMO3, GPD1L, EDNRB, RNASE1, PDK4, CAT, and MAL showed strong diagnostic contributions, among which ADRB2 displayed particular mechanistic relevance. Immune-infiltration and single-cell RNA-sequencing analyses suggested that ADRB2 was associated with multiple immune-cell populations and was distributed across both malignant and immune-cell compartments within the PM microenvironment, while molecular docking indicated potential interactions between asbestos and multiple core proteins. LDH assays showed that 2.5 μg/cm2 represented a low-to-subtoxic exposure concentration in MeT-5A and MSTO-211H cells. At this concentration, all three asbestos types promoted proliferation, clonogenic growth, and invasion and up-regulated ADRB2, with crocidolite exerting the strongest effect. Mechanistically, ADRB2 knockdown attenuated crocidolite-induced IL-17/NF-κB-related signalling, reduced IL-6, CXCL1, and CXCL8 expression, and suppressed the malignant phenotype of MSTO-211H cells, whereas recombinant human IL-17A partially restored these effects. These findings identify ADRB2 as a potential diagnostic and mechanistic target in asbestos-related PM and suggest that ADRB2 may contribute to crocidolite-induced malignant progression by modulating cellular responses associated with IL-17/NF-κB-related inflammatory signalling.
Shaoyang Huang, Dandan Gu, Jintao He et al.· Chemico-Biological Interacti...· 0 citations
Background Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor of the digestive system with a very low five-year survival rate. The limited efficacy and significant toxicity of existing chemotherapy regimens make the development of novel natural therapeutic agents an urgent priority. Lycopene is a natural carotenoid that has been shown to inhibit multiple cancers. However, research specifically targeting PDAC remains relatively scarce. Methods This study first employed bibliometric analysis to examine the research landscape and emerging trends in lycopene-related cancer research from 2016 to 2026. Subsequently, network pharmacology methods are applied to screen potential lycopene targets and PDAC-related targets from databases such as CTD, ChEMBL and HERB. Following the identification of overlapping targets, drug-target and protein–protein interaction (PPI) networks are constructed, as well as a disease network. The mechanisms were explored using Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Molecular docking was used to predict the potential interactions between lycopene and representative hub targets, and molecular dynamics simulations were performed for selected high-ranking docking complexes to provide supportive information on complex-level conformational stability. In vitro experiments were then conducted to evaluate the predicted anti-PDAC effects and to perform focused validation of apoptosis-related proteins and the PI3K/Akt/P53 signaling axis. Results Publications on lycopene research in the field of cancer have shown a sustained upward trend. The focus of this research has gradually shifted from areas such as oxidative stress and antioxidant effects towards anti-cancer mechanisms. A total of 132 overlapping targets for lycopene’s anti-PDAC activity were screened, leading to the identification of 10 core targets, including BCL2, AKT1, and TP53. GO enrichment analysis revealed that these targets are involved in biological processes such as the response to oxidative stress and cellular senescence. Meanwhile, KEGG enrichment analysis identified the PI3K-Akt signaling pathway as a key pathway. Molecular docking results showed that the binding energies of lycopene with core targets such as TP53 and BCL2 were below −4.5 kcal/mol. Molecular dynamics simulations provided supportive evidence for the conformational stability of representative lycopene-target complexes. In vitro experiments showed that lycopene inhibited the proliferation and migration of PDAC cells and promoted apoptosis-associated cell death, accompanied by decreased p-PI3K and p-AKT expression and increased P53 expression. Conclusion This study systematically combined bibliometrics, network pharmacology, molecular docking, representative molecular dynamics simulations, and focused experimental validation to explore the potential anti-PDAC activity of lycopene. The inflammation-related hub targets identified by network analysis provide additional hypotheses for future experimental investigation. These findings provide preliminary mechanistic evidence for further preclinical investigation of lycopene in PDAC, but its translational application will require optimized formulations, pharmacokinetic validation, and in vivo efficacy studies to overcome its limited bioavailability.
Shaoyang Huang, Dandan Gu, Dan Song et al.· Frontiers in Nutrition· 0 citations
